Method of treating side effects induced by therapeutic agents

Abstract

The invention relates to agents for the prevention of organ damage, in particular of the kidneys and the inner ear, induced by the administration of aminoglycosides. Agents according to the invention are all substances which are megalin and / or cubilin antagonists (inhibitors). In particular, these are molecules (compounds) having polybasic structures which bind to megalin and inhibit the binding of aminoglycosides and related substances.

Description

[0001]The invention relates to agents for the prevention of organ damage, in particular of the kidneys and the inner ear, induced by the administration of therapeutic agents.BACKGROUND[0002]It is known that aminoglycosides are some of the most important antibiotics for the treatment of severe bacterial infections. They are the preferred agents against a number of Gram-negative bacteria. Their annual market potential in Germany is about 500 million DM. At present, the market share of the aminoglycosides in the field of anti-infectious agents is even rapidly increasing. This is above all due to the general increase in the occurrence of pathological strain resistance to other classes of antibiotics.[0003]The main obstacle in the clinical use of aminoglycosides is their severe oto- and nephrotoxic side effects which especially lead to complete loss of hearing and to renal failure in the long term. The use of aminoglycosides is thus not only associated with a high risk, but also entails ...

AI Technical Summary

Benefits of technology

[0012]Thus, it is an object of the invention to provide substances capable of reducing or inhibiting the accumulation of aminoglycosides as well as other toxic medicaments in cells, in particular in the kidneys and the inner ear and, in order to avoid damage to organs consisting of the cells.

[0018]Cubilin is a receptor colocalizing with megalin, that may facilitate the endocytic process of megalin by sequestering the therapeutic agent on the cellular surface before megalin-mediated internalization of the cubilin-bound ligand.

Problems solved by technology

The main obstacle in the clinical use of aminoglycosides is their severe oto- and nephrotoxic side effects which especially lead to complete loss of hearing and to renal failure in the long term.

The use of aminoglycosides is thus not only associated with a high risk, but also entails high resulting costs.

As aminoglycosides are only weakly degradable in the cells, they accumulate in large numbers and lead to destruction of the cell structures and thus to renal damage and loss of hearing.

Various surface structures or receptors have been made responsible for the binding and uptake of the antibiotics; however, a clear demonstration of the binding sites of aminoglycosides on the body cells has not yet been possible.

However, Moestrup et al. could only show the binding of aminoglycosides to megalin in test tubes and in cultivated cells.

However, as aminoglycosides are only taken up into the organism in the kidneys and in the inner ear, the value of these in vitro experiments is unclear.

However, they led to an increase in the treatment costs.

However, this use is also connected with a further increase in the therapy costs as amikacin (DM 180 per day) is clearly more expensive than usual gentamicin compositions (DM 35 per day).

In general it is doubtful whether this strategy of changing aminoglycoside has any effect at all, since a direct correlation between bactericidal effect and toxic effect is seen.

So far, none of these uses have been implemented clinically.

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